Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center in Houston. And it's a distinct pleasure to welcome today, Dr. Jeremy Teoh, all the way from Hong Kong. Dr. Teoh is an Assistant Professor at the Chinese University of Hong Kong. He is the Director of the Urology Center at the Medical Center and is very active in multiple aspects of clinical oncology, especially when it comes to bladder cancer. One of his recent projects that was published was on delving deeper into the recurrence mechanisms of non-muscle invasive bladder cancer in a clinical perspective. And it's a pleasure to welcome Dr. Teoh today. Jeremy, with that, the stage is yours.

Jeremy Teoh: Thank you very much, Dr. Kamat. It's always a pleasure to join you. Today I'm going to give a summary about a paper that we published recently, and it's about the recurrence mechanism of non-muscle invasive bladder cancer from a clinical perspective. So, it's well known bladder cancer usually presents early with visible hematuria. And usually when patient present to us, they to present with an early-stage disease, non-muscle invasive bladder cancer. Which means that most of the time, surgery should be able to obtain a cure. A good resection, where we're able to clear the cancer cell completely, then we should be able to obtain a cure. Unfortunately what we observe is that the oncological outcomes of non-muscle invasive bladder cancer following surgery is actually not very good. The one-year cancer rate has been quoted between 15% to 61%. And the five-year, it's 31% to 78%.

So, this really troubles me. Because being an early-stage disease, the surgery should be enough to obtain a cure, but then while we observe such a high recurrence rate. So I always try to think, what are the possible ways that these cancer actually recur, despite a complete resection? In this paper, we summarize the different mechanisms of tumor recurrence. And namely would be undetected cancer, local residual disease after surgery, tumor re-implantation, drop metastasis from UTUC cancer, as well as field change cancerization. And I'm going to briefly discuss about these mechanisms one by one in this presentation.

First, it's about the undetected cancer. As you all know, a good surgery starts with a good and comprehensive inspection, we must be able to visualize the tumor before we resect it completely. Unfortunately, sometimes the cancer changes can be very subtle. As you can see, a white light cystoscopy, sometimes change is really difficult to identify. But with the use of enhanced imaging, for example narrow band imaging are for, to direct diagnosis, MH1S, et cetera, these abnormal areas can be visualized quite nicely and therefore a good resection can be done. And these, this is a very simple way to kind of facilitate your detection of cancer and allowing a better resection.

And second mechanism is about the local residual disease after surgery. Conventional TURBT is done with a piecemeal resection, resect from the top to the bottom of the tumor. Unfortunately during the procedure, there's really a lack of a uniform resection of a tumor bed. It's really difficult to ascertain a complete tumor resection based on endoscopic vision alone, and there are multiple studies showing that residual disease can occur despite a so-called complete tumor resection. If we leave some tumors behind, and obviously these tumors will persist and appear as a recurrence on surveillance cytoscopy. And again, there are several ways in where we can try to tackle this mechanism. Certain patients have T1 disease, for example, we often would offer a second TURBT.

There are some proposals in trying to optimize the resection procedure. For example, ampullary resection of bladder tumor. Some kind of imaging, for example, MRI scan can also help diagnose muscle-invasive disease. These tumors will be directed to cystectomy directly instead of having TURBT, which is associated with problems in terms of the local staging as well. Now of course, TURBT although it may sound like it's the surgery. But surgical training and also quality performance indicator programs are also important to improve the resection quality, then hopefully the oncological outcomes can be optimized.

And third mechanism will be tumor re-implantation, during the resection. Because we resect the tumor in piecemeal manner, inevitably there will be a lot of tumor cells within the bladder. Although we try to evacuate these tumor fragments after surgery, but inevitably there will still be something. Tumor cells within the bladder, and these cells may actually implant to the bladder mucosa and causing early disease recurrence. And therefore some maneuvers, for example the use of a single-dose postoperative instillation of chemotherapy has been shown to improve the cancer outcome. There are also some studies showing that if we try to give a continuous bladder irrigation after the surgery, this may also help dilute the cells within the bladder and hopefully actually improve the cancer outcome in long term.

The fourth mechanism will be the possible drop metastasis from the initial upper tract cancer. Of course these patients presented with hematuria at the beginning, so most of the time we would have upper tract imaging to route upper tract urothelial carcinoma. But if we really miss a tumor in the upper tract, that obviously these tumors will, may actually drop into the bladder and cause an apparent tumor recurrence after the initial TURBT. So CT urogram will be a very good imaging modality to try to rule out upper tract cancers, but of course other imaging such as MR urogram is also possible.

And the last mechanism is about the field change cancerization effect. As we all know, tobacco smoking is the major risk factor for urothelial carcinoma. And the reason is that after smoking is a source carcinogens. These carcinogens after being absorbed into the body, they will be excreted through the kidneys in the urine. The bladder being an organ for urine storage, it's actually persistently exposed to these urine carcinogens 24 hours a day. Therefore the bladder is really, really prone to the development, of bladder cancer development. Even after a good surgery, there can be other tumors, new tumors growing from other sites of the bladder as well. So, this is also a mechanism that we must deal with.

And having said that, there are many different types of mechanism of recurrence. I think the key point is that we need to identify them clearly, we need to know the different ways that we can tackle each mechanisms. And in this paper we summarize the different maneuvers, as well as the evidence that we have in the literature supporting each treatment options. I think it's really a good summary trying to show how we can optimize outcomes from a urologist's perspective. To sum up, I think understanding the recurrence mechanism from a clinical perspective is really important to optimize the outcomes. Because I really believe that a cure for patients with non-muscle invasive bladder cancer can only be achieved if we are able to tackle all possible recurrence mechanism in a comprehensive manner. If you're interested, and please feel free to read this paper, published in the Nature Reviews Urology recently. Hopefully you will find it very informative and we can, it will actually help you your practice. So, this is pretty much that I've prepared. Dr. Kamat?

Ashish Kamat: So thank you, Jeremy, for that presentation. And you covered the key points in your didactic part of the conversation today. Let me pivot a little bit and ask you of all the things that you mentioned, what would you say in your opinion is the low hanging fruit? And again, you mentioned that. But if you had to talk to both trainees and experienced urologists, what would you say we should focus on? One, two and three?

Jeremy Teoh: Yeah. That's exactly why I try to list these mechanisms out, because I wanted to know which is the predominant mechanism causing recurrence. I think we need to look into this by the evidence really, and I think the most important mechanism that we must deal with is actually local residual disease. Because in high-risk diseases in particular, cyclic surgery has been shown to detect residual cancer in 20%, 30% of the cases. And this is really, really high. And if we have ways to improve or at least ensure a good resection during surgery, if we can eliminate this 20% to 30% chance of residual cancer, then the recurrence rate hopefully will be a lot lower.

The second thing that I think is really, really difficult to tackle would be the field change cancerization effect. Especially when it comes to the background of the bladder wall or the biology of a tumor. I mean if you do a perfect surgery, you can hopefully reduce the early recurrence rate. But in terms of the long-term recurrence rate, when the biology of a tumor or the field change cancerization effect comes into place, then we really need some kind of immunotherapy or novel immune agents that can actually help us control the disease in long run. And these two mechanisms, in my opinion, are the most important ones to address.

And of course under that, the cancer, in terms of the use of enhanced imaging is something that is very easy to do for us. So, we certainly can do that. And for the tumor re-implantation part, of course we give chemo, we can also consider ampullary resection trying to reduce the risk of flowing tumor cells as well. But these two mechanisms, in my opinion, probably are less important. But the least important was definitely, will be the drop metastasis. Because the incidence of upper tract cancer by itself is very low, when compared to bladder cancer.

Ashish Kamat: So, you bring up an interesting point. And it's something that I have been involved with for many, many years, as you have as well now. There are folks in Europe and Hugh Mostafid and Jim Catto and Bernie Bochner in the US, have really been trying to champion a good TURBT as the first primary step in the care of patients with bladder cancer. And we have patient advocacy groups that have recognized the importance of this and have been making this better known to their patients, per se. But we still find that a lot of patients that are referred to our center have had, unfortunately suboptimal resection of the tumor. You go in and it's not just that there's residual tumor, but sometimes there's obvious tumor that's been missed. So how are you in your center in Hong Kong tackling the education of trainees, in order to provide them the best skills available for TURBT?

Jeremy Teoh: Yeah, I think this is a very important question. And in fact, I think the problem, it's something it's combination of technical factors. Meaning that whether you can have a good resection down to the muscle layer, whether you can identify the muscle layer clearly during a resection. And the other thing, which unfortunately in my opinion is about the mindset and attitude of the surgeon. How many times have we seen surgeons actually rushing through the surgery? I mean trying to do, inspect just not very comprehensively, just trying to respect it very quickly and finish the surgery? Inevitably the quality will be kind of compromised and in fact, their cancer outcomes as well.

The way to do it is number one, I think we must emphasize that this is a cancer surgery. We should respect it as a cancer surgery, and it deserves a lot more time during the surgery to try to ensure the quality. And we should really embrace a systematic approach in doing a surgery. And of course TURBT by itself can be systematic, but at our center we do a lot of ampullary resection as well. Ampullary resection by its definition is the removal of tumor in one piece. But I think what's more important is really defining the procedure in a stepwise manner, trying to define the margins, trying to ensure that you go into the muscle layer circumferentially and then tackling the central part of the tumor base.

It's more a systematic approach in doing a surgery, and we find that it can actually improve the outcomes of the surgery. Say the presence of muscle in the specimen, the presence of clear margins during ... after the surgery et cetera. Last but not least, I think a good surgical training program as well as regular audits probably will help. Because surgeons may take this surgery very lightly. But once they see the outcomes, they realize that there are some areas for improvement. And hopefully with time, their oncological outcomes can also be improved.

Ashish Kamat: Yeah. And again, this remains a challenge, right? Because there are so many courses and lectures and workshops that are held at multiple meetings for things, such as robotic cystectomy. Which is clearly important, but it's not the most important thing for our patients. And then TURBT is kind of ... get relegated to, in some places. Residents teaching residents or the juniormost residents doing it, and they don't really get the skillset. So, I'm glad that you're incorporating those things into your training program.

The next question I wanted to ask you was this whole concept of en bloc resection. Which has been around now for many, many years and it hasn't really gained much to traction. And of course, you and I recognize why. I mean a lot of it is based on the fact that if you resect a large enough tumor, then it's a problem to get it out en bloc. Because the tools don't exist. But for our viewers and listeners, what are some of the key clinical pearls you would want to leave them with when it comes to how to do en bloc resection in their practice?

Jeremy Teoh: Yeah, I think you mentioned a very good point. That for big tumors, even if we're able to resect it in one piece, we may not be able to take it out in one piece. But having done the procedure for so many times, I think removal of one piece, it sounds very good. But it's not, in my opinion, the main point of a surgery really. Because the whole procedure is about getting into the muscle layer circumferentially, and then tackling the center part, making sure that you reach the muscle layer at every part of the resection bed. And whether you take it out in multiple pieces, it doesn't really matter. Because it's the resection procedure that matters. And that's why I think it's important procedure that can actually ensure a complete local resection, rather than so-called removal in one piece.

In our center, we have actually done some kind of audits. We try to apply this procedure routinely for our patients, regardless of tumor size. We found that about 85% of patients are actually amenable for ampullary recession, and the reason is because most of time these patients present rather early. And so, the tumor size may not be so big. Because this surgery is really focused on non-muscle invasive bladder cancer, so most of the time this surgery is actually feasible. And I think it's more about a surgical principle. If we remove the tumor, of course we try to remove in one piece. We try to avoid fragmenting it. Want to ensure a complete resection, not based on endoscopic vision alone, but based on the histological finding of a clear resection margin.

So, it's a principle that we should try to uphold. It doesn't mean that we can do that all the time. But as far as feasible, I think where it's something that we should embrace. But having said that, we still need randomized trial to show the benefit of the surgery. And there are a number of clinical trials ongoing, then hopefully in the coming two or three years we'll more evidence to show that. Where the ampullary resection, it's really the way to go.

Ashish Kamat: Right. Now one thing that you didn't mention, and I suspect you didn't mention that for a specific reason. But when it comes to decreasing recurrence rates, there are clearly things that we can do when it comes to the surgeon or the treating physician, which you outlined really well. Then there's tumor biology, which clearly we have to recognize the field effect and the upper tract, and so on and so forth. But the one thing that really affects recurrence rates when it comes to patients is optimal treatment of the surrounding bladder, once you've resected the tumor. Or in CIS, the actual residual CIS because it's hard to visualize or resect all of the CIS.

And when it comes to that, there's a wide variation in recommendations in different regions, countries, guidelines. And obviously, it depends upon the risk stratification of the patient. Are they low-risk, intermediate-risk or high-risk? But if you were to again in a nutshell make recommendations for optimal intravesical therapy, BCG for high-risk patients for example ... recognizing there's a shortage, maybe chemotherapy for low-risk patients. What would you advise our listeners in our audience, on selecting the best treatment for the appropriate patient at the appropriate time? What would be your summary statement?

Jeremy Teoh: Yeah. So I think in these patients, CIS for example, these are really high risk of having recurrence. And I think the adoption of immunotherapy, for example intravesical BCG, is very important to ensure a good oncological outcome. And of course, some of the centers may give a maintenance type of intravesical chemotherapy. I tend to think that these chemo, this type of agent is more cytotoxic, it's not really affecting the immunomodulation part. So to ensure a long-term durable type of response, I still think immunotherapy, it's better. But I think what's more exciting would be the use of say, PD-L1 inhibitors or other gene-mediated viral therapy, whether these medications can actually perform even better than conventional intravesical BCG therapy. Of course, we'll need a lot more clinical data on this. But right now at this moment, I would say intravesical BCG is still the standard of care for patients with such a bad disease.

Ashish Kamat: Right. So once again, Jeremy, thank you so much for taking the time and spending it with us. And this paper is very provocative and timely, of course. And I urge everyone to go and read it, if they can get their hands on it. If not, I'm sure we can put a link to the publication. But again, I want to thank you for taking the time and spending it with us today. Hopefully we'll get, have a chance to see each other soon.

Jeremy Teoh: Thank you very much, my pleasure.